The central goal of this program project is to elucidate integrative principles regulating brain development by defining sequential ontogenetic processes. We are pursuing the unifying concept that seemingly distinct developmental processes, including neuronal mitosis, aggregation, transmitter and receptor gene expression and trophic interactions with the formation of synaptic circuits are causally interrelated. Although several of these events have been examined in some detail, causal mechanistic relationships among these processes remain unclear. Our studies are now defining critical interactions among these phenomena. We are finding that a number of molecules integrate successive developmental processes through intercellular communication. We will employ multidisciplinary molecular genetic, biochemical, pharmacologic and morphologic approaches to study neuronal development in vivo and in culture. We plan to define a) factors regulating neuronal mitosis, focusing on insulin, a neuronal mitogen recently identified by us; b) regulation of expression of the NGF (nerve growth factor) receptor gene, recently cloned by us; c) mechanisms governing transmitter receptor expression; d) membrane factors governing transmitter phenotypic expression and e) NGF regulation of the formation of brain circuits. Our overall objective is to define molecular mechanistic relations among these apparently diverse developmental processes. Such insights may indicate how seemingly discrete, sequential events causally lead to orderly brain development. This information may define molecular loci where disease processes intervene, leading to abnormal brain development, birth defects and mental retardation.